Numerous therapeutic agents are poorly soluble in an aqueous medium. Conventional formulations that incorporate unmilled or non-micronized forms of these therapeutic agents suffer from several disadvantages such as incomplete dissolution, slow dissolution and/or highly variable dissolution profiles. Furthermore, following oral administration, these conventional formulations exhibit low and/or variable bioavailability. To compensate for low bioavailability, the dose is often increased in these formulations. Dosage increases, however, still do not address the problems associated with highly variable inter- and/or intra-subject bioavailability. Thus, conventional formulations of hydrophobic drugs are frequently required to be taken with meals in order to address poor bioavailability, in addition to the variability associated with the bioavailability encountered with these drugs. As a result, however, patient compliance is often low as patients may forget to administer these formulations with meals or decide to skip a dose when the patient is not willing to consume an entire meal.
Poor patient compliance, in turn, requires frequent monitoring and dosage adjustments by the treating clinician. In particular, these disadvantages are evidenced with several families of lipid-regulating agents, such as fibrates and statins.
Fenofibrate (2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethylester) is a well known lipid-regulating agent from the fibrate family. The active metabolite of fenofibrate, fenofibric acid, produces reductions in total cholesterol, low density lipoprotein (LDL), apolipoprotein B, total triglycerides and very low density lipoprotein (VLDL). In addition, treatment with fenofibrate results in increases in high density lipoprotein (HDL). 
Fenofibrate is hydrophobic in nature (see structure shown above) and is practically insoluble in water. Fenofibrate has been commercially available under the names Lipanthyl, Lipidil® and Lipantil. Although the usual daily dose is as high as 300-400 mg, the product is nonetheless poorly absorbed in the gastrointestinal tract of patients. As a result, it is poorly and variably bioavailable and must be taken with food.
One approach in producing pharmaceutically acceptable fenofibrate hydrophobic formulations involves the use of micronization. U.S. Pat. No. 4,895,726 to Curtet et al. discloses a composition and method of improving the dissolution, and consequently, the bioavailability, of fenofibrate by using a solid surfactant that is co-micronized with fenofibrate. U.S. Pat. No. 5,880,148 to Edgar et al. also discloses a combination of a micronized mixture of fenofibrate with a solid surfactant and a vitamin E substances. This combination is stated to be useful as an antiatheromatous drug and to exhibit a synergistic effect by protecting plasma LDL from oxidation. U.S. Pat. No. 4,800,079 to Boyer et al. discloses a controlled-release formulation of fenofibrate based on specially designed granules. Each granule contains an inert core, a fenofibrate layer and a protective layer. The formulation is characterized in that fenofibrate is present in the form of crystalline microparticles of dimensions not greater than 30 microns. The microparticles are included within the pores of an inert matrix. U.S. Pat. No. 6,074,670 to Stamm et al. discloses an immediate-release fenofibrate composition comprising an inert hydrosoluble carrier covered with at least one layer containing fenofibrate in a micronized form having a size less than 20 microns.
In the United States, fenofibrate is currently available under the name Tricor®. This fenofibrate formulation is available in capsule form and contains 67 mg of micronized fenofibrate. Each capsule also contains lactose, pregelatinized starch, sodium lauryl sulfate, crospovidone and magnesium stearate. The bioavailability of fenofibrate is significantly improved over the non-micronized forms, thus reducing the daily maximum dose of fenofibrate in this formulation to 200 mg. However, it still requires administration of three capsules daily, which can result in patient inconvenience. Furthermore, the absorption of fenofibrate from Tricor® is heavily influenced by the presence of food , thus requiring Tricor® to be administered with meals to optimize bioavailability. The number of capsules per day, meal requirements and variability in bioavailability all present significant patient compliance challenges in the management of lipid disorders.
The preparation of fenofibrate in the form of crystalline microparticles or that of co-micronizing fenofibrate with a solid surfactant is a time consuming and costly process. An inherent drawback of micronization is that the material obtained must comply with stringent particle size specifications for quality and performance. In addition, processes that require the production of coating layers and inert matrixes are also complex, time consuming and costly. Furthermore, the handling and filling of capsules with a micronized powder present challenges with regard to safety and ensuring uniformity of the active agent throughout the formulation. Most importantly, a micronized microparticle or a co-micronized mixture containing fenofibrate requires complete and consistent dissolution of the drug as a prerequisite for the effective absorption of fenofibrate and to obtain a satisfactory bioavailability profile.
Other approaches for producing fenofibrate formulations have been described. U.S. Pat. No. 5,827,536 to Laruelle discloses a fenofibrate formulation containing fenofibrate in solution of a solubilizing agent consisting of a non-ionic surfactant, diethylene glycol monoethyl ether (DGME).
U.S. Pat. No. 5,545,628 to Deboeck et al. discloses pharmaceutical compositions for treating hyperlipidemia or hypercholesterolemia or both in a mammal. The compositions contain fenofibrate and an excipient containing one or more polyglycolyzed glycerides. The polyglycolzed glycerides are generally mixtures of known monoesters, diesters and triesters of glycerols and known monoesters and diesters of polyethylene glycol with a mean relative molecular mass between 200 and 6000. They may be obtained by partial transesterification of triglycerides with polyethylene glycol or by esterification of glycerol and polyethylene glycol with fatty acids.
U.S. Pat. No. 6,096,338 to Lacy et al. discloses a carrier for hydrophobic drugs, e.g., fenofibrate, that contains a digestible oil and a pharmaceutically acceptable surfactant for dispersing the oil in vivo upon administration of the carrier. The surfactant comprises a hydrophilic surfactant component which substantially inhibits the in vivo lipolysis of the digestible oil and a lipophilic surfactant component capable of at least substantially reducing the inhibitory effect of the hydrophilic surfactant component. The lipophilic surfactant component is present in an amount sufficient to achieve the required counteracting of the lipolysis-inhibiting properties of the hydrophilic surfactant component.
WO 99/29300A1 discloses a self-emulsifying preconcentrate containing fenofibrate dissolved in a carrier system comprising a hydrophobic component, a surfactant and a hydrophilic component. Each of these approaches, however, has individual drawbacks.
Therefore, for more effective and economic disease management, there is an ongoing need for improved fenofibrate formulations. In particular, there is a need for fenofibrate formulations that are not dependent on the micronization of fenofibrate or the co-nicronization of fenofibrate with a solid surfactant for effective absorption. Such formulations are more easily administered, e.g., administered without regard to meals (to enhance patient compliance), adequately bioavailable and less costly to manufacture and commercialize.